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Article

Functional Roles of CD26/DPP4 in Bleomycin-Induced Pulmonary Hypertension Associated with Interstitial Lung Disease

by
Tadasu Okaya
1,
Takeshi Kawasaki
1,*,
Shun Sato
1,2,
Yu Koyanagi
1,
Koichiro Tatsumi
1,
Ryo Hatano
3,
Kei Ohnuma
3,
Chikao Morimoto
3,
Yoshitoshi Kasuya
4,
Yoshinori Hasegawa
5,
Osamu Ohara
5 and
Takuji Suzuki
1,2
1
Department of Respirology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
2
Synergy Institute for Futuristic Mucosal Vaccine Research and Development, Chiba University, Chiba 260-8670, Japan
3
Department of Therapy Development and Innovation for Immune Disorders and Cancers, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan
4
Department of Biomedical Science, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
5
Department of Applied Genomics, Kazusa DNA Research Institute, Chiba 292-0818, Japan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2024, 25(2), 748; https://doi.org/10.3390/ijms25020748
Submission received: 24 November 2023 / Revised: 30 December 2023 / Accepted: 4 January 2024 / Published: 6 January 2024
(This article belongs to the Special Issue Molecular Advances and Perspectives of Lung Disease)
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Abstract

Pulmonary hypertension (PH) with interstitial lung diseases (ILDs) often causes intractable conditions. CD26/Dipeptidyl peptidase-4 (DPP4) is expressed in lung constituent cells and may be related to the pathogenesis of various respiratory diseases. We aimed to clarify the functional roles of CD26/DPP4 in PH-ILD, paying particular attention to vascular smooth muscle cells (SMCs). Dpp4 knockout (Dpp4KO) and wild type (WT) mice were administered bleomycin (BLM) intraperitoneally to establish a PH-ILD model. The BLM-induced increase in the right ventricular systolic pressure and the right ventricular hypertrophy observed in WT mice were attenuated in Dpp4KO mice. The BLM-induced vascular muscularization in small pulmonary vessels in Dpp4KO mice was milder than that in WT mice. The viability of TGFβ-stimulated human pulmonary artery SMCs (hPASMCs) was lowered due to the DPP4 knockdown with small interfering RNA. According to the results of the transcriptome analysis, upregulated genes in hPASMCs with TGFβ treatment were related to pulmonary vascular SMC proliferation via the Notch, PI3K-Akt, and NFκB signaling pathways. Additionally, DPP4 knockdown in hPASMCs inhibited the pathways upregulated by TGFβ treatment. These results suggest that genetic deficiency of Dpp4 protects against BLM-induced PH-ILD by alleviating vascular remodeling, potentially through the exertion of an antiproliferative effect via inhibition of the TGFβ-related pathways in PASMCs.
Keywords: CD26; dipeptidyl peptidase-4; pulmonary hypertension; interstitial lung disease CD26; dipeptidyl peptidase-4; pulmonary hypertension; interstitial lung disease

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MDPI and ACS Style

Okaya, T.; Kawasaki, T.; Sato, S.; Koyanagi, Y.; Tatsumi, K.; Hatano, R.; Ohnuma, K.; Morimoto, C.; Kasuya, Y.; Hasegawa, Y.; et al. Functional Roles of CD26/DPP4 in Bleomycin-Induced Pulmonary Hypertension Associated with Interstitial Lung Disease. Int. J. Mol. Sci. 2024, 25, 748. https://doi.org/10.3390/ijms25020748

AMA Style

Okaya T, Kawasaki T, Sato S, Koyanagi Y, Tatsumi K, Hatano R, Ohnuma K, Morimoto C, Kasuya Y, Hasegawa Y, et al. Functional Roles of CD26/DPP4 in Bleomycin-Induced Pulmonary Hypertension Associated with Interstitial Lung Disease. International Journal of Molecular Sciences. 2024; 25(2):748. https://doi.org/10.3390/ijms25020748

Chicago/Turabian Style

Okaya, Tadasu, Takeshi Kawasaki, Shun Sato, Yu Koyanagi, Koichiro Tatsumi, Ryo Hatano, Kei Ohnuma, Chikao Morimoto, Yoshitoshi Kasuya, Yoshinori Hasegawa, and et al. 2024. "Functional Roles of CD26/DPP4 in Bleomycin-Induced Pulmonary Hypertension Associated with Interstitial Lung Disease" International Journal of Molecular Sciences 25, no. 2: 748. https://doi.org/10.3390/ijms25020748

APA Style

Okaya, T., Kawasaki, T., Sato, S., Koyanagi, Y., Tatsumi, K., Hatano, R., Ohnuma, K., Morimoto, C., Kasuya, Y., Hasegawa, Y., Ohara, O., & Suzuki, T. (2024). Functional Roles of CD26/DPP4 in Bleomycin-Induced Pulmonary Hypertension Associated with Interstitial Lung Disease. International Journal of Molecular Sciences, 25(2), 748. https://doi.org/10.3390/ijms25020748

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